title: In vivo real-time monitoring system of electroporation mediated control of transdermal and topical drug delivery.
abstract: Electroporation (EP) is a physical method for the delivery of molecules into cells and tissues, including the skin. In this study, in order to control the degree of transdermal and topical drug delivery, EP at different amplitudes of electric pulses was evaluated. A new in vivo real-time monitoring system based on fluorescently labeled molecules was developed, for the quantification of transdermal and topical drug delivery. EP of the mouse skin was performed with new non-invasive multi-array electrodes, delivering different amplitudes of electric pulses ranging from 70 to 570 V, between the electrode pin pairs. Patches, soaked with 4 kDa fluorescein-isothiocyanate labeled dextran (FD), doxorubicin (DOX) or fentanyl (FEN), were applied to the skin before and after EP. The new monitoring system was developed based on the delivery of FD to and through the skin. FD relative quantity was determined with fluorescence microscopy imaging, in the treated region of the skin for topical delivery and in a segment of the mouse tail for transdermal delivery. The application of electric pulses for FD delivery resulted in enhanced transdermal delivery. Depending on the amplitude of electric pulses, it increased up to the amplitude of 360 V, and decreased at higher amplitudes (460 and 570 V). Topical delivery steadily enhanced with increasing the amplitude of the delivered electric pulses, being even higher than after tape stripping used as a positive control. The non-invasive monitoring of the delivery of DOX, a fluorescent chemotherapeutic drug, qualitatively and quantitatively confirmed the effects of EP at 360 and 570 V pulse amplitudes on topical and transdermal drug delivery. Delivery of FEN at 360 and 570 V pulse amplitudes verified the observed effects as obtained with FD and DOX, by the measured physiological responses of the mice as well as FEN plasma concentration. This study demonstrates that with the newly developed non-invasive multi-array electrodes and with the varying electric pulse amplitude, the amount of topical and transdermal drug delivery to the skin can be controlled. Furthermore, the newly developed monitoring system provides a tool for rapid real-time determination of both, transdermal and topical delivery, when the delivered molecule is fluorescent.
authors.affiliation: Department of Experimental Oncology, Institute of Oncology Ljubljana, Zaloska 2, SI-1000 Ljubljana, Slovenia.
authors.forename: Tanja
authors.initials: T
authors.lastname: Blagus
authors.forename: Bostjan
authors.initials: B
authors.lastname: Markelc
authors.forename: Maja
authors.initials: M
authors.lastname: Cemazar
authors.forename: Tina
authors.initials: T
authors.lastname: Kosjek
authors.forename: Veronique
authors.initials: V
authors.lastname: Preat
authors.forename: Damijan
authors.initials: D
authors.lastname: Miklavcic
authors.forename: Gregor
authors.initials: G
authors.lastname: Sersa
mesh_terms: D000759:Adjuvants, Anesthesia / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D000279:Administration, Cutaneous; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D003911:Dextrans / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D004317:Doxorubicin / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D016503:Drug Delivery Systems / Q000295:instrumentation*; D018274:Electroporation / Q000295:instrumentation*; D005260:Female; D005283:Fentanyl / Q000008:administration & dosage*; D016650:Fluorescein-5-isothiocyanate / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D051379:Mice; D008807:Mice, Inbred BALB C; D012867:Skin / Q000378:metabolism; D012869:Skin Absorption
chemical_list: D000759:Adjuvants, Anesthesia; D000903:Antibiotics, Antineoplastic; D003911:Dextrans; C015219:fluorescein isothiocyanate dextran; D004317:Doxorubicin; D016650:Fluorescein-5-isothiocyanate; D005283:Fentanyl
keywords: Controlled delivery; Electroporation; Monitoring system; Multi-array electrodes; Topical drug delivery; Transdermal drug delivery